TY - JOUR
T1 - CD33
T2 - Increased inclusion of exon 2 implicates the Ig V-set domain in Alzheimer's disease susceptibility
AU - Raj, Towfique
AU - Ryan, Katie J.
AU - Replogle, Joseph M.
AU - Chibnik, Lori B.
AU - Rosenkrantz, Laura
AU - Tang, Anna
AU - Rothamel, Katie
AU - Stranger, Barbara E.
AU - Bennett, David A.
AU - Evans, Denis A.
AU - De Jager, Philip L.
AU - Bradshaw, Elizabeth M.
N1 - Funding Information:
This work is supported by the National Institutes of Health (F32 AG043267, R01 AG031553, R01 AG30146, R01 AG17917, R01 AG15819, P30 AG10161, R01 AG11101, R01 NS067305, RC2 GM093080 and R01 AG043617).
PY - 2014/5
Y1 - 2014/5
N2 - We previously demonstrated that the Alzheimer's disease (AD) associated risk allele, rs3865444C, results in a higher surface density of CD33 on monocytes. Here, we find alternative splicing of exon 2 to be the primary mechanism of the genetically driven differential expression of CD33 protein. We report that the risk allele, rs3865444C, is associated with greater cell surface expression of CD33 in both subjects of European and African-American ancestry and that there is a single haplotype influencing CD33 surface expression. A meta-analysis of the two populations narrowed the number of significant SNPs in high linkage disequilibrium (LD) (r2 > 0.8) with rs3865444 to just five putative causal variants associated with increased protein expression. Using gene expression data from flow-sorted CD14+CD16- monocytes from 398 healthy subjects of three populations, we show that the rs3865444C risk allele is strongly associated with greater expression of CD33 exon 2 (pMETA = 2.36 × 10-60). Western blotting confirms increased protein expression of the full-length CD33 isoform containing exon 2 relative to the rs3865444C allele (P < 0.0001). Of the variants in strong LD with rs3865444, rs12459419, which is located in a putative SRSF2 splice site of exon 2, is the most likely candidate to mediate the altered alternative splicing of CD33's Immunoglobulin V-set domain 2 and ultimately influence AD susceptibility.
AB - We previously demonstrated that the Alzheimer's disease (AD) associated risk allele, rs3865444C, results in a higher surface density of CD33 on monocytes. Here, we find alternative splicing of exon 2 to be the primary mechanism of the genetically driven differential expression of CD33 protein. We report that the risk allele, rs3865444C, is associated with greater cell surface expression of CD33 in both subjects of European and African-American ancestry and that there is a single haplotype influencing CD33 surface expression. A meta-analysis of the two populations narrowed the number of significant SNPs in high linkage disequilibrium (LD) (r2 > 0.8) with rs3865444 to just five putative causal variants associated with increased protein expression. Using gene expression data from flow-sorted CD14+CD16- monocytes from 398 healthy subjects of three populations, we show that the rs3865444C risk allele is strongly associated with greater expression of CD33 exon 2 (pMETA = 2.36 × 10-60). Western blotting confirms increased protein expression of the full-length CD33 isoform containing exon 2 relative to the rs3865444C allele (P < 0.0001). Of the variants in strong LD with rs3865444, rs12459419, which is located in a putative SRSF2 splice site of exon 2, is the most likely candidate to mediate the altered alternative splicing of CD33's Immunoglobulin V-set domain 2 and ultimately influence AD susceptibility.
UR - http://www.scopus.com/inward/record.url?scp=84898770218&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddt666
DO - 10.1093/hmg/ddt666
M3 - Article
C2 - 24381305
AN - SCOPUS:84898770218
SN - 0964-6906
VL - 23
SP - 2729
EP - 2736
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 10
M1 - ddt666
ER -